Individually tailored Internet-delivered cognitive-behavioral therapy for survivors of intimate partner violence: A randomized controlled pilot trial.

Intimate partner violence (IPV) is a serious public health concern worldwide and defined as behavior performed by spouses or other intimate partners that causes physical, sexual, or psychological harm. Internet-delivered cognitive-behavioral therapy (ICBT) may be particularly useful for survivors of IPV for several reasons, including barriers pertaining to limited community recourses and treatment availability, safety concerns, and issues of stigma, guilt and shame, which may prevent members of this population from seeking help via face-to-face interactions. However, Internet interventions are lacking. The primary aim of the present randomized controlled pilot trial was to explore the feasibility of ICBT as guided self-help individually tailored to the predominant symptomatology of PTSD or depression in survivors of IPV. A second aim was to conduct a preliminary evaluation exploring the short- and long-term effects of the treatment in comparison to a waitlist control condition. Results showed that the treatment was feasible. Attrition rate was low (9.4%), and participants were satisfied with treatment. However, treatment adherence was moderate in terms of completed modules (62.5%). Results of the preliminary evaluation of treatment effects showed large and statistically significant between-group effect sizes (Cohen's d = 0.86-1.08) on some measures of PTSD and depression at post assessment, favoring the treatment condition. However, there were no effects on other measures. At follow-up assessment, when the control condition had received delayed treatment, there were large and statistically significant within-group effect sizes (d = 0.96-1.48) on measures of PTSD, depression and anxiety, and small effects (d = 0.48) on a measure of quality of life. The results of the present pilot study are promising and warrant further research on ICBT for this population.

Combined prenatal Lactobacillus reuteri and ω-3 supplementation synergistically modulates DNA methylation in neonatal T helper cells.

BACKGROUND: Environmental exposures may alter DNA methylation patterns of T helper cells. As T helper cells are instrumental for allergy development, changes in methylation patterns may constitute a mechanism of action for allergy preventive interventions. While epigenetic effects of separate perinatal probiotic or ω-3 fatty acid supplementation have been studied previously, the combined treatment has not been assessed. We aimed to investigate epigenome-wide DNA methylation patterns from a sub-group of children in an on-going randomised double-blind placebo-controlled allergy prevention trial using pre- and postnatal combined Lactobacillus reuteri and ω-3 fatty acid treatment. To this end, > 866000 CpG sites (MethylationEPIC 850K array) in cord blood CD4+ T cells were examined in samples from all four study arms (double-treatment: n = 18, single treatments: probiotics n = 16, ω-3 n = 15, and double placebo: n = 14). Statistical and bioinformatic analyses identified treatment-associated differentially methylated CpGs and genes, which were used to identify putatively treatment-induced network modules. Pathway analyses inferred biological relevance, and comparisons were made to an independent allergy data set. RESULTS: Comparing the active treatments to the double placebo group, most differentially methylated CpGs and genes were hypermethylated, possibly suggesting induction of transcriptional inhibition. The double-treated group showed the largest number of differentially methylated CpGs, of which many were unique, suggesting synergy between interventions. Clusters within the double-treated network module consisted of immune-related pathways, including T cell receptor signalling, and antigen processing and presentation, with similar pathways revealed for the single-treatment modules. CpGs derived from differential methylation and network module analyses were enriched in an independent allergy data set, particularly in the double-treatment group, proposing treatment-induced DNA methylation changes as relevant for allergy development. CONCLUSION: Prenatal L. reuteri and/or ω-3 fatty acid treatment results in hypermethylation and affects immune- and allergy-related pathways in neonatal T helper cells, with potentially synergistic effects between the interventions and relevance for allergic disease. Further studies need to address these findings on a transcriptional level, and whether the results associate to allergy development in the children. Understanding the role of DNA methylation in regulating effects of perinatal probiotic and ω-3 interventions may provide essential knowledge in the development of efficacious allergy preventive strategies. Trial registration ClinicalTrials.gov, ClinicalTrials.gov-ID: NCT01542970. Registered 27th of February 2012-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01542970 .

Involvement of fear, incompleteness, and disgust during symptoms of pediatric obsessive-compulsive disorder.

Fear has been assigned a central role in models of obsessive-compulsive disorder (OCD), but empirical investigations into the emotions that underpin OCD symptoms are few, especially in pediatric samples. Using validated, clinician-led structured interviews, 124 youth with OCD reported on the presence and severity of symptoms across the main symptom dimensions of OCD (aggressive, symmetry, contamination) and the degree to which fear, incompleteness, and disgust accompanied these symptoms. For comparison purposes, the degree of fear, incompleteness, and disgust during symptoms was obtained also from youth with social anxiety disorder (SAD; n = 27) and generalized anxiety disorder (GAD; n = 28). Participants with OCD reported that all three emotions were involved in their symptoms; however, fear was most strongly linked to aggressive symptoms, incompleteness to symmetry symptoms, and disgust to contamination symptoms. Incompleteness differentiated youth with OCD from those with SAD and GAD. No differences for these emotions were found for youth with OCD with versus without the tic-disorder subtype or comorbid autism. A positive association between incompleteness and self-reported hoarding emerged among youth with OCD. Further studies of the emotional architecture of pediatric OCD, and its relationship to etiology and treatment, are warranted.

Incompleteness, harm avoidance, and disgust: A comparison of youth with OCD, anxiety disorders, and no psychiatric disorder.

Psychological models of pediatric obsessive-compulsive disorder (OCD) place a heavy emphasis on harm avoidance as a maintaining factor and target for treatment. Incompleteness and disgust may also play a role in pediatric OCD but remain understudied. Youth with OCD (n = 100), anxiety disorders (n = 96), and no impairing psychiatric symptoms (n = 25) completed self-report measures of trait-level incompleteness, harm avoidance, and disgust and current symptoms of OCD, anxiety, and depression. Group differences and associations between emotions, symptoms, and pre- to post-treatment change in overall OCD severity were examined. Youth with OCD and anxiety disorders scored higher on harm avoidance and disgust than youth with no psychiatric disorder. Youth with OCD scored higher on incompleteness than youth with anxiety disorders and youth with no psychiatric disorder. Harm avoidance showed unique associations to self-reported symptoms of OCD, anxiety, and depression while incompleteness was uniquely related to OCD and disgust to anxiety. Within the OCD sample, incompleteness and harm avoidance were differentially related to the major OCD symptom dimensions, and change in incompleteness was uniquely related to pre- to post-treatment change in OCD severity. Trait-level incompleteness appears to play a central role in pediatric OCD and studies investigating its direct involvement in symptoms and associations with treatment outcome are needed. The role of disgust in relation to pediatric OCD remains unclear.

The Centrality of Doubting and Checking in the Network Structure of Obsessive-Compulsive Symptom Dimensions in Youth.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a heterogeneous condition with well-established symptom dimensions across the lifespan. The objective of the present study was to use network analysis to investigate the internal structure of these dimensions in unselected schoolchildren and in children with OCD. METHOD: We estimated the network structure of OCD symptom dimensions in 6,991 schoolchildren and 704 children diagnosed with OCD from 18 sites across 6 countries. All participants completed the Obsessive-Compulsive Inventory-Child Version. RESULTS: In both the school-based and clinic-based samples, the OCD dimensions formed an interconnected network with doubting/checking emerging as a highly central node, that is, having strong connections to other symptom dimensions in the network. The centrality of the doubting/checking dimension was consistent across countries, sexes, age groups, clinical status, and tic disorder comorbidity. Network differences were observed for age and sex in the school-based but not the clinic-based samples. CONCLUSION: The centrality of doubting/checking in the network structure of childhood OCD adds to classic and recent conceptualizations of the disorder in which the important role of doubt in disorder severity and maintenance is highlighted. The present results suggest that doubting/checking is a potentially important target for further research into the etiology and treatment of childhood OCD.

Validation of an interview-only version of the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) in treatment-seeking youth with obsessive-compulsive disorder.

There is a growing body of evidence suggesting that individuals with obsessive-compulsive disorder (OCD) may be sub-typed along different symptom dimensions. These dimensions may help explain responsiveness to current treatments. The Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) is a validated instrument involving a self-report screening tool followed by a structured interview in which the presence/absence and severity of OCD symptom dimensions are assessed and rated. The present study investigated the validity of a briefer, interview-only version of the DY-BOCS modified for use in routine care. Clinically-referred children and adolescents (N = 119) with OCD were administered the DY-BOCS along with other measures of OCD, anxiety, depression, and overall functioning and a subset (N = 100) were reassessed on average 14 months after initial assessment. This briefer, interview-only version of the DY-BOCS demonstrated high levels of internal consistency and correlated in the moderate to strong range with alternative measures of OCD severity and OCD symptom dimensions. Change scores on the DY-BOCS from baseline to follow-up were significantly correlated with change scores on the alternative measures of OCD and clinician-rated improvement, suggesting that this brief version of the DY-BOCS is valid and sensitive to the effects of treatment for OCD delivered in routine clinical care.

Role of the NMDA-receptor in Prepulse Inhibition in the Rat.

Kynurenic acid (KYNA) is an endogenous metabolite of tryptophan. Studies have revealed increased brain KYNA levels in patients with schizophrenia. Prepulse inhibition (PPI) is a behavioral model for sensorimotor gating and found to be reduced in schizophrenia. Previous studies have shown that pharmacologically elevated brain KYNA levels disrupt PPI in the rat. The aim of the present study was to investigate the receptor(s) involved in this effect. Rats were treated with different drugs selectively blocking each of the sites that KYNA antagonizes, namely the glutamate recognition site of the N-methyl-D-aspartate receptor (NMDAR), the α7* nicotinic acetylcholine receptor (α7nAChR) and the glycine site of the NMDAR. Kynurenine (200 mg/kg) was given to replicate the effects of increased levels of KYNA on PPI. In order to block the glutamate recognition site of the NMDAR, CGS 19755 (10 mg/kg) or SDZ 220-581 (2.5 mg/kg) were administered and to antagonize the α7nAChR methyllycaconitine (MLA; 6 mg/kg) was given. L-701,324 (1 and 4 mg/kg) or 4-Chloro-kynurenine (4-Cl-KYN; 25, 50 and 100 mg/kg), a drug in situ converted to 7-Chloro-kynurenic acid, were used to block the glycine-site of the NMDAR. Administration of SDZ 220-581 or CGS 19755 was associated with a robust reduction in PPI, whereas L-701,324, 4-Cl-KYN or MLA failed to alter PPI. Kynurenine increased brain KYNA levels 5-fold and tended to decrease PPI. The present study suggests that neither antagonism of the glycine-site of the NMDA receptor nor antagonism of the α7nAChR disrupts PPI, rather with regard to the effects of KYNA, blockade of the glutamate recognition-site is necessary to reduce PPI.

Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: implications for schizophrenia.

Kynurenic acid (KYNA) is an endogenous compound implicated in the pathophysiology of schizophrenia. This tryptophan metabolite antagonizes both the N-methyl-D-aspartate (NMDA) receptors and the nicotinic alpha7* receptors at micromolar concentrations. In the present study the effects of amphetamine on dopamine (DA) release in the nucleus accumbens and on firing of DA neurons in the ventral tegmental area (VTA) were investigated in rats treated with kynurenine, the precursor of KYNA, in order to elevate brain KYNA levels. In rats subchronically treated with kynurenine (90 mg/kg x d for 6 d via osmotic minipumps, resulting in a 2-fold increase in whole-brain KYNA), the amphetamine-induced (2 mg/kg i.p.) increase in accumbal DA release was clearly enhanced compared to controls. Furthermore, subchronic treatment with kynurenine reduced the inhibitory action of amphetamine (0.2-25.6 mg/kg i.v.) on firing rate and burst firing activity of VTA DA neurons. A single dose of kynurenine (5 mg/kg s.c., 60 min, resulting in a 3-fold increase in whole-brain KYNA) did not alter the amphetamine-induced effects on DA neurotransmission compared to control rats. Present data are in agreement with the increased striatal DA release by amphetamine as observed by brain-imaging studies in patients with schizophrenia. Thus, subchronic elevation of rat brain KYNA, may rationally serve as an animal model similar to a pathophysiological condition of schizophrenia. It is proposed that the reduced responsivity of VTA DA neurons to the inhibitory action of amphetamine observed in rats with subchronically elevated KYNA levels may partly account for the increase in terminal DA release.

Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis.

Kynurenic acid (KYNA) is an endogenous NMDA receptor antagonist as well as a blocker of the alpha7* nicotinic receptor and mounting evidence suggests that the compound participates in the pathophysiology of schizophrenia. Previous studies have shown that elevated levels of endogenous KYNA are associated with an increased firing of midbrain dopamine (DA) neurons. In the present study, utilizing extracellular single unit cell recording techniques, the mechanism involved in this excitatory action of the compound was analyzed in male Sprague-Dawley rats. Administration of 4-chlorokynurenine (4-Cl-KYN; 25mg/kg, i.p.), which is converted to the selective NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), was found to increase firing rate and per cent burst firing activity of ventral tegmental area (VTA) DA neurons to the same magnitude as pretreatment of kynurenine (causing a 25-fold elevation in extracellular brain KYNA). Intravenous administration of the selective antagonist at the alpha7* nicotinic receptor methyllycaconitine (MLA; 1-4mg/kg) did not affect firing of VTA DA neurons, whereas intraperitoneal administration of this drug in a high dose (6mg/kg) was associated with a decreased firing rate and per cent burst firing activity. Administration of SDZ 220-581 (10mg/kg, i.v.), a competitive antagonist at the glutamate recognition-site of the NMDA receptor, was found to increase firing rate and per cent burst firing. Present results have potential implications for the treatment of schizophrenia, and indicate that the increased activity of VTA DA neurons following elevation of brain KYNA is mediated through glutamatergic rather than by nicotinergic mechanisms.